Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease

Abstract

Purpose Infantile Pompe disease resulting from a deficiency of lysosomal acid α-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients. Methods Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA. Results In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts. Conclusion The combination of rituximab with methotrexate ± intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the naïve setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy.

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

“…IgG-mediated immune responses in patients with infantile-onset Pompe disease (IPD) using ITI strategies [18,19,20]. However, this strategy has not yet been adopted in other LSDs, where immune responses also occur, but where the clinical impact of such responses on efficacy and safety of ERTs is less clear.…”

“…Thus, we should consider CRIM status also as a continuum, from CRIM-negative at one end to strongly CRIMpositive at the other end of the spectrum. Effectively mitigating the immune response to ERT is thus an area of therapeutic intervention where potential improvements can be made to significantly improve clinical outcomes [18,19,48,49]. An important focus in the future is the early identification of patients with Pompe disease who are at greatest risk of developing HSAT subsequent to ERT initiation.…”

Transient Low-Dose Methotrexate Induces Tolerance to Murine Anti-Thymocyte Globulin and Together They Promote Long-Term Allograft Survival

“…This effect is being evaluated in the clinical setting where patients treated with a combination of rituximab and an immune tolerizing regimen of methotrexate appear to develop immune tolerance to the enzyme replacement therapy, Myozyme (38,39). These observations were extended further in the studies reported in this paper, which demonstrated that a single cycle of methotrexate treatment can effectively induce immune tolerance to anti-drug Abs and control Ab responses to multiple protein Ags simultaneously in a transplantation setting.…”

Guidelines for the diagnosis, treatment and clinical monitoring of patients with juvenile and adult Pompe disease

“…In these circumstances, there is a decline of the therapeutic response to ERT (walking, lung function, SF-36) and adverse events associated to ERT may be observed 32 (B). Currently, immune modulation and immune suppression protocols, in an attempt to reduce neutralizing antibodies against rhGAA, have been successfully applied in infantile onset PD patients with high sustained IgG antibodies 42 . Patients with PDJ-A are CRIM-positive and therefore are less likely to have such serious immunological reactions 32 .…”